Establishment of curative therapy for Alzheimer's disease with Humanin peptides

本研究发现并报道了Humanin （HN）对阿尔茨海默病（AD）相关成人的神经保护作用机制和AD相关神经元细胞死亡的新机制，特别是发现了淀粉样前体蛋白（APP）的天然和神经元细胞死亡诱导配体1。HN的神经保护机制2001年，我们发现HN由24个氨基酸组成，并通过AD相关的损伤，如家族性AD （FAD）相关的APP突变体、早老素-1 （PS1）突变体、PS2突变体、神经毒性淀粉样蛋白-β肽，抑制神经元细胞死亡。HN的神经保护功能尚不完全清楚。我们成功地获得了不具有神经保护活性但具有自二聚化活性的hn衍生物。因此，这些衍生物（P3A, L12A， S14A和P19A）可以作为HN拮抗剂。到目前为止，一种典型的酪氨酸激酶抑制剂genetistein可以抑制HN活性，以对抗v642i - app诱导的F11神经杂交细胞死亡。因此，我们使用了多种激酶抑制剂和突变基因，这些基因可以作为显性阴性形式。我们发现信号换能器和转录3 （STAT3）参与了HN对ad相关损伤诱导的神经元细胞死亡的神经保护活性。这些表明，假定的HN受体复合物位于STAT3的上游，并与某些酪氨酸激酶有关。这些结果对鉴定HN受体复合物和模拟HN作用的小化合物具有重要意义。ad相关神经元细胞死亡的分子机制目前，我们发现并报道了一种针对APP胞外结构域的单克隆抗体22C11可以诱导神经元细胞死亡。此外，我们报道了百日破毒素（PTX）敏感的Go蛋白、Gβγ蛋白、c-Jun n末端激酶、NADPH氧化酶和caspase-3/相关caspase参与神经元细胞死亡。通过各种结合实验和细胞死亡实验，我们发现转化生长因子β2 （tgf - β2）结合APP的胞外结构域，通过APP以PTX敏感的方式诱导神经元细胞死亡。此外，我们报道了18月龄雌性Tg2576阿尔茨海默病模型小鼠皮质M1区tgf - β2的蛋白表达。从这些结果来看，TGFb2可能参与了AD的发病。p75神经营养因子受体（p75NTR）是引起神经元细胞死亡的a β受体候选物。2002年，Frankowski等人发现PLAIDD分子与p75NTR相似。因此，我们试图研究PLAIDD在Aβ/ p75ntr诱导的神经元细胞死亡中的作用。由此我们得出结论，PTX敏感的Gi蛋白结合到PLAIDD和Aβ/p75NTR/PLAIDD的胞内结构域与Aβ/p75NTR一样可以触发神经元细胞死亡。少

In this research term, we found and reported that the mechanism of Humanin (HN) neuroprotective activity against Alzheimer's disease (AD)-relevant indults and the novel AD-relevant neuronal cell death mechanisms, especially we found the natural and neuronal cell death inducible ligand for amyloid precursor protein (APP).1.The mechanisms of HN neuroprotectionIn 2001, we found HN which is consisted of 24 amino acids, and inhibited neuronal cell death by AD-relevant insults such as familial AD (FAD)-linked APP mutants, presenilin-1 (PS1) mutants, PS2 mutants, neurotoxic amyloid-β peptides. It is not fully understood the HN neuroprotective functions. We succeeded HN-derivatives which have no neuroprotective activity but have its self-dimerization activity. So, these derivatives (P3A, L12A, S14A, and P19A) can act as HN antagonists.Until now, genetistein, a typical tyrosine kinase inhibitor, inhibited HN activity against V642I-APP-induced F11 neurohybrid cell death. Therefore, we used vario … More us kinase inhibitors and mutant genes which can act as dominant negative forms. We identified the involvement of signal transducer and transcription 3 (STAT3) in HN neuroprotective activity against AD-relevant insults induced neuronal cell death. These indicated that the putative receptor complex for HN is upstreams of STAT3 and related to certain tyrosine kinases. These results are important for the identification of HN receptor complex and small compound which can mimic HN action.2.The molecular mechanisms of AD-relevant neuronal cell deathUntil now, we found and reported that 22C11, a monoclonal antibody developed against extracellular domain of APP, can induce neuronal cell death. In addition, we reported that pertussis toxin (PTX) sensitive Go protein, Gβγ proteins, c-Jun N-terminal kinase, NADPH oxidase, and caspase-3/related caspase are involved in the neuronal cell death. By various binding experiments and cell death experiments, we found that transforming growth factor β2 (TGFβ2) binds to the extracellular domain of APP and induce the neuronal cell death via APP in PTX sensitive manner. In addition, we reported that the protein expression of TGFβ2 in cortex M1 region of 18-months-old female Tg2576 Alzheimer's disease model mouse. From these results, there is a possibility that TGFb2 is involved in the onset of AD.The p75 neurotrophin receptor (p75NTR) is a candidate for Aβ receptor which can cause neuronal cell death. In 2002, PLAIDD molecule has been identified by Frankowski et al., and is similar to p75NTR. Therefore, we attempted to investigated the involvement of PLAIDD in Aβ/p75NTR-induced neuronal cell death. From the results, we concluded that PTX sensitive Gi proteins bind to the intracellular domain of PLAIDD and Aβ/p75NTR/PLAIDD can trigger the neuronal cell death as same as Aβ/p75NTR. Less